The solubility behavior of a drug is a key determinant of its bioavailability. Solubility presents a challenge to the development of a suitable formulation for drugs. With the recent advent of high throughput screening of potential therapeutic agents, the number of poorly soluble drug candidates has risen sharply and the formulation of poorly soluble compounds now presents one of the most frequent and greatest challenges to formulation scientists in the pharmaceutical industry.
The production of drug delivery systems by melt extrusion of a polymer/active ingredient mixture is known in the art. In general, such processes Examples of such drug delivery systems are generally described in the U.S. patents set forth in Table 1.
TABLE 1U.S. Pat. No.TitleYearU.S. Pat. No. 5456923Method of manufacturing solid dispersion1995U.S. Pat. No. 5665369Fast-dispensing solid PVP-containing crop1997protection formulation and processU.S. Pat. No. 5939099Solid active extrusion compound prepara-1999tions containing low-substituted hydroxy-propylcelluloseU.S. Pat. No. 5958452Extruded orally administrable opioidformulations1999U.S. Pat. No. 6051253Production of solid drug forms2000U.S. Pat. No. 6120802Method of producing multi-layer medica-2000ments in solid form for oral or rectaladministration
In general, the basic ingredients of a drug delivery system comprise (1) one or more pharmaceutically active ingredients (polymers); (2) one or more polymer binders; and (3) pharmaceutically acceptable ancillaries, plasticizers, and the like. Generally, active ingredients do not decompose at extrusion temperatures. Pharmaceutical auxiliaries may include plasticizers, fillers, lubricants, flow regulators, colorant, stabilizers, and the like, and are typically not affected by the process conditions. However, polymer carrier or binder components are preferably thermally stable so that they are not decomposed at extrusion temperatures. If such carriers or binder components are melt-extruded, they are preferably thermoplastic.
In general, the formulation of the polymer or the polymer mixture controls the active ingredient profile required by the end user. Examples of the manipulation of polymer carriers to control active ingredient profiles and release rates are set forth in, e.g., U.S. Pat. No. 5,665,369 to Wedlock (crop protection formulation, where rapid release is critical; PVP is used as a polymer binder); U.S. Pat. No. 5,939,099 to Grabowski (mixture of thermoplastic water soluble polymer and water insoluble, swellable, non-thermoplastic polymer L-HPC used to control the active ingredient release rate; and U.S. Pat. No. 5,958,452 to Oshlack (mixture of hydrophobic polymer and hydrophobic fusible carrier used in an orally administrable opioid formulation, where hydrophobic fusible carrier slows down the release of the active agents).
In general, the process for creating drug delivery systems to which the present invention relate comprises (1) a preparation step, wherein the ingredients of the drug mixture are mixed and melting or softened; (2) an extrusion step and, optionally, a (3) cooling or shaping step.
During the first preparation step, a common challenge is obtaining a homogeneous dispersion of the active ingredients in polymer binders. U.S. Pat. No. 5,456,592 to Nakamichi et al. describes the use of a twin-screw extruder to improve the process to obtain solid dispersion. “Solid dispersion” or “solid solution” generally refers to a mixture in which the active ingredient is present in the form of a molecular dispersion in the polymer. The twin-screw extruder consists of a metering feeder unit, a barrel, screws, exit dies, etc. Such extruders enhance the mixing process by creating high shear forces, transport capacity and compounding effects. Hence, the production of a solid dispersion can be obtained at lower temperature allowing the use of thermally sensitive ingredients. In addition, such extruders generate lower heats of friction than single screw extruders.
After preparation, drug mixtures are extruded through a suitable die. The mixture is melted or softened at the extrusion temperature. The shape of the die depends on the desired shape of drug formulation. Coextrusion dies may be used for multiple-layer drug production as set forth in U.S. Pat. No. 6,120,802 to Breitenbach.
The extruded drug mixture strand is solidified by cooling. The solid drug can be formed through a shaping process before or after the components are solidified. After cooling, the strand can be cut or divided into multiparticulates of desired size and divided into unit doses (see, e.g., U.S. Pat. No. 5,939,099). U.S. Pat. No. 6,051,253 to Zettler describes direct solid drug formation by splitting a drug mixture strand and then rounding-off the end of the strand before the extrudate is solidified. U.S. Pat. No. 6,120,802 to Breitenbach describes a one-step direct shaping process such that the extrudate is cut into the final tablet shape immediately after the extrusion, with the cutter/shaper being located downstream of the extruder die.